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A Gain‐of‐Function Mutation in KCNMA1 Causes Dystonia Spells Controlled With Stimulant Therapy
Author(s) -
Zhang Guohui,
Gibson Rebecca A.,
McDonald Marie,
Liang Pengfei,
Kang Po Wei,
Shi Jingyi,
Yang Huanghe,
Cui Jianmin,
Mikati Mohamad A.
Publication year - 2020
Publication title -
movement disorders
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.352
H-Index - 198
eISSN - 1531-8257
pISSN - 0885-3185
DOI - 10.1002/mds.28138
Subject(s) - dystonia , stimulant , exome sequencing , medicine , movement disorders , mutation , psychology , neuroscience , genetics , biology , disease , gene
Background The mutations of KCNMA1 BK‐type K + channel have been identified in patients with various movement disorders. The underlying pathophysiology and corresponding therapeutics are lacking. Objectives To report our clinical and biophysical characterizations of a novel de novo KCNMA1 variant, as well as an effective therapy for the patient's dystonia‐atonia spells. Methods Combination of phenotypic characterization, therapy, and biophysical characterization of the patient and her mutation. Results The patient had >100 dystonia‐atonia spells per day with mild cerebellar atrophy. She also had autism spectrum disorder, intellectual disability, and attention deficit hyperactivity disorder. Whole‐exome sequencing identified a heterozygous de novo BK N536H mutation. Our biophysical characterization demonstrates that N536H is a gain‐of‐function mutation with markedly enhanced voltage‐dependent activation. Remarkably, administration of dextroamphetamine completely suppressed the dystonia‐atonia spells. Conclusions BK N536H is a gain‐of‐function that causes dystonia and other neurological symptoms. Our stimulant therapy opens a new avenue to mitigate KCNMA1 ‐linked movement disorders. © 2020 International Parkinson and Movement Disorder Society